Inactivation of DNA-Dependent Protein Kinase by Protein Kinase Cδ: Implications for Apoptosis |
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| Authors: | Ajit Bharti Stine-Kathrein Kraeft Mrinal Gounder Pramod Pandey Shengfang Jin Zhi-Min Yuan Susan P. Lees-Miller Ralph Weichselbaum David Weaver Lan Bo Chen Donald Kufe Surender Kharbanda |
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| Affiliation: | Cancer Pharmacology1. and Cancer Biology,2. Dana-Farber Cancer Institute, and Department of Microbiology and Molecular Genetics,3. Harvard Medical School, Boston, Massachusetts 02115; Department of Biological Sciences University of Calgary, Calgary, Alberta, Canada T2N IN44.; and Department of Radiation and Cellular Oncology University of Chicago, Chicago, Illinois 606375. |
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| Abstract: | Protein kinase Cδ (PKCδ) is proteolytically cleaved and activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Fas antibody. A role for PKCδ in apoptosis is supported by the finding that overexpression of the catalytic fragment of PKCδ (PKCδ CF) in cells is associated with the appearance of certain characteristics of apoptosis. However, the functional relationship between PKCδ cleavage and induction of apoptosis is unknown. The present studies demonstrate that PKCδ associates constitutively with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The results show that PKCδ CF phosphorylates DNA-PKcs in vitro. Interaction of DNA-PKcs with PKCδ CF inhibits the function of DNA-PKcs to form complexes with DNA and to phosphorylate its downstream target, p53. The results also demonstrate that cells deficient in DNA-PK are resistant to apoptosis induced by overexpressing PKCδ CF. These findings support the hypothesis that functional interactions between PKCδ and DNA-PK contribute to DNA damage-induced apoptosis. |
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